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Abstract:

A mixer for mixing a fluid having a property varying along a flow
direction of the fluid includes an inlet configured for receiving an
inlet flow, an outlet configured for providing an outlet flow, and a
plurality of flow channels coupled between the inlet and the outlet. The
mixer also includes a flow distributor for distributing the inlet flow
into the plurality of flow channels so that each flow channel receives a
partial flow from the inlet flow, and a flow combiner for combining the
partial flows from the plurality of flow channels to the outlet flow.
Each flow channel has a first flow section having a hydraulic resistance
substantially representing a hydraulic resistance of the flow channel.
One or more of the flow channels each have a second flow section coupled
in series with the first flow section of the respective flow channel.

Claims:

1. A mixer for mixing a fluid having a property varying along a flow
direction of the fluid, the mixer comprising: an inlet configured for
receiving an inlet flow, an outlet configured for providing an outlet
flow, and a plurality of flow channels coupled between the inlet and the
outlet, a flow distributor for distributing the inlet flow into the
plurality of flow channels so that each flow channel receives a partial
flow from the inlet flow, and a flow combiner for combining the partial
flows from the plurality of flow channels to the outlet flow, wherein
each flow channel comprises a first flow section having a hydraulic
resistance substantially representing a hydraulic resistance of the flow
channel, one or more of the flow channels each comprise a second flow
section coupled in series with the first flow section of the respective
flow channel, each second flow section comprises a volume that is flown
through by the fluid and delays fluid propagation from the first flow
section to the flow combiner by a time required by the respective partial
flow to pass the volume of the respective second flow section, and the
distribution of the partial flows into the flow channels is substantially
independent of the viscosity of the fluid.

2. The mixer of claim 1, comprising at least one of: the hydraulic
resistance of each of the plurality of flow channels is substantially
equal; the volume of the second flow section is significantly larger than
a volume of the first flow section of the respective flow channel; the
distribution of the partial flows into the flow channels is substantially
independent of the viscosity of the fluid at any moment in time.

3. The mixer of claim 1, comprising at least one of: the flow distributor
distributes the fluid into the first flow sections of the plurality of
flow channels; the flow distributor substantially simultaneously
distributes the fluid into the first flow sections; a variation of the
property of the fluid arrives substantially simultaneously at the first
flow sections.

4. The mixer of claim 1, comprising at least one of: the flow-through
times of the partial flows through the first flow sections are
substantially equal; the flow-through times of the partial flows through
the first flow sections are substantially neglectable to a characteristic
duration of a variation of the varying property of the fluid; the
flow-through times of the partial flows through the first flow sections
are substantially equal and neglectable to a characteristic duration of a
variation of the varying property of the fluid; the flow-through time of
each partial flow through the respective first flow section is smaller
than a characteristic duration of a variation of the varying property of
the fluid.

5. The mixer of claim 1, comprising at least one of: a plurality of the
second flow sections each has a different volume for delaying the partial
flow of the respective flow channel by a different time period; the
volume of each of a plurality of the second flow sections is configured
so that the output flow has a desired flow delay profile with respect to
the input flow; the volume of each second flow section is significantly
larger than a volume of the first flow section of the respective flow
channel.

6. The mixer of claim 1, comprising at least one of: one or more of the
second flow sections each comprises a chamber; one or more of the second
flow sections each comprises a plurality of chambers arranged
sequentially in the flow direction of the fluid and having a total volume
being significantly larger than a volume of the first flow section of the
respective flow channel.

7. The mixer of claim 1, wherein: one or more of the second flow sections
each comprises a plurality of chambers arranged sequentially in the flow
direction of the fluid, wherein successive chambers are coupled by a
respective connecting section.

8. The mixer of claim 7, comprising at least one of: each chamber has an
average cross section being significantly larger than an average cross
section of a respective connecting section coupled to such chamber; each
chamber has a chamber volume being significantly larger than a volume of
a respective connecting section coupled to such chamber; wherein a
plurality of the connecting sections are arranged with respect to the
respective chambers to force the fluid to flow at varying angles with
respect to direction of gravitational force.

9. The mixer of claim 1, wherein one or more of the second flow sections
each comprises at least one direction change element configured for
changing the flow direction of the fluid.

10. The mixer of claim 9, wherein the direction change element comprises
at least one first subsection having a first direction of flow of the
fluid, and at least one second subsection having a second direction of
flow of the fluid, the first direction of flow being inclined with
respect to the second direction of flow.

11. The mixer of claim 10, comprising at least one of: the first
direction of flow is vertical and the second direction of flow is
horizontal; at least one of the first and second directions of flow has a
direction component in the direction of gravitational force.

12. The mixer of claim 1, comprising at least one of: each flow channel
comprises a respective first flow section and a respective second flow
section coupled in series, the hydraulic resistance of the first flow
section being significantly larger than a hydraulic resistance of the
second flow section thus dominating the hydraulic resistance of the flow
channel; the hydraulic resistance of the first flow section is in the
range of 2-100000 times, preferably 5-500 times, and more preferably
about -100 times, larger than the hydraulic resistance of the second flow
section; in each flow channel, a first cross section of the first flow
section is significantly smaller than a second cross section of the
second flow section thus dominating the hydraulic resistance of the flow
channel.

13. The mixer of claim 1, comprising at least one of: each first flow
section is substantially equal in length in flow direction of the fluid;
the fluid is at least one of a liquid and a gas; the varying property of
the fluid is at least one of a physical and chemical property varying
along the flow direction of the fluid; the varying property of the fluid
is at least one of temperature, composition, viscosity, and elution
strength varying along the flow direction of the fluid.

14. A mixer for mixing a fluid having a property varying along a flow
direction of the fluid, the mixer comprising: an inlet configured for
receiving an inlet flow, an outlet configured for providing an outlet
flow, and a plurality of flow channels coupled between the inlet and the
outlet, a flow distributor for distributing the inlet flow into the
plurality of flow channels so that each flow channel receives a partial
flow from the inlet flow, and a flow combiner for combining the partial
flows from the plurality of flow channels to the outlet flow, wherein
each flow path comprises a flow direction change forcing the fluid to
flow at varying angles with respect to a direction of gravitational in
the consequent sub-sections of the flow path.

15. A fluid separation system for separating compounds of a sample fluid
in a mobile phase, the fluid separation system comprising: a mobile phase
drive configured to drive the mobile phase through the fluid separation
system, a separation unit configured for separating compounds of the
sample fluid in the mobile phase, a mixer according to claim 1.

16. The fluid separation system of claim 15, further comprising at least
one of: the mixer is arranged in a flow path between the mobile phase
drive and the separation unit; a sample injector configured to introduce
the sample fluid into the mobile phase; a detector configured to detect
separated compounds of the sample fluid; a collection unit configured to
collect separated compounds of the sample fluid; a data processing unit
configured to process data received from the fluid separation system; a
degassing apparatus configured for degassing the mobile phase.

Description:

BACKGROUND

[0001] The present invention relates to a flow distribution mixer
distributing the inlet flow into a plurality of flow channels and then
combining the partial flows from the plurality of flow channels to the
outlet flow, in particular for high performance liquid chromatography
application.

[0002] In high performance liquid chromatography (HPLC), a liquid has to
be provided usually at a very well controlled flow rate (e.g. in the
range of microliters to milliliters per minute), at a very well
controlled composition (e.g. in the range of 0.3% or better) and at high
pressure (typically 20-100 MPa, 200-1000 bar, and beyond up to currently
200 MPa, 2000 bar) at which compressibility of the liquid becomes
noticeable. For liquid separation in an HPLC system, a mobile phase
comprising a sample fluid containing compounds to be separated is driven
through a stationary phase (e.g. contained in a chromatographic column),
thus separating different compounds of the sample which may then be
identified.

[0003] The mobile phase, for example, a solvent, is pumped under high
pressure typically through a column filled with packing material, and the
sample (e.g. a chemical or biological mixture) to be analyzed is injected
into the stream of the mobile phase and with that is transported to the
column. As the sample passes through the column driven by the liquid
flow, the different compounds, each one having a different affinity for
the packing medium, move through the column with different velocities.
Those compounds having higher affinity to the stationary phase (e.g. a
packing medium) move more slowly through the column than those having
lower affinity, and this velocity differences results in the compounds
being separated from one another as they pass through the column.

[0004] During operation, a flow of the mobile phase, typically driven by a
high pressure chromatographic pump, traverses the column filled with the
stationary phase, and due to the interactions between the mobile, the
stationary phase and sample components a separation of different
compounds may be achieved. As a result of flow passing through the
stationary phase and depending on the physical properties of the
stationary phase and the mobile phase, a relatively high pressure drop
takes place along the column. The composition of the mobile phase is in
many cases controlled by the pump operation, as the pump blends single
flows of mobile phase constituents according to the pump settings or
program. These flows are then combined together to provide a mixed flow
of the mobile phase or eluent. The composition and the flow rate of the
mobile phase are usually precisely controlled.

[0005] The fluctuations of the mixing ratio in an eluent flow generated
e.g. by an HPLC pump can lead to undesired base line noise, bad
reproducibility of the analysis or to separation performance
deterioration. For certain applications, e.g. separations using eluents
with UV-absorbing additives, the strict requirements to the constancy or
smoothness of the eluent composition over the separation time cannot be
satisfied without using additional mixing appliances which disperse the
zones with fluctuations of the eluent composition.

[0006] U.S. Pat. No. 6,629,775 B2, by the same applicant, discloses a
mixing apparatus wherein a fluid is progressing from an inlet tubing to
an outlet tubing. Every segment of the liquid is part by part transferred
to the outlet channel via numerous restrictor channels. The distances
between the restrictor channels determine a dispersion pattern for any
segment of the flow, progressing from the inlet chamber in the form of a
reservoir channel to the outlet. The nearer the outlet channels are
placed one to another, the higher is the permeability to the outlet
collector at the respective location. Delaying partial flows of the fluid
with different flow delays and providing different flow volumes for the
partial flows results in a predetermined flow distribution function thus
determining a dispersion pattern. This allows for a continuous dispersion
of a fluid property which is intended to be mixed, for instance to be
homogenized, in accordance with a predefined fluid distribution function.

SUMMARY

[0007] It is an object of the invention to provide an improved flow
distribution mixer, in particular for HPLC applications. The object is
solved by the independent claim(s). Further embodiments are shown by the
dependent claim(s).

[0008] According to embodiments of the present invention, a mixer is
provided for mixing a fluid (which may be a liquid and/or a gas) having a
property varying along a flow direction of the fluid. The mixer comprises
an inlet configured for receiving an inlet flow, an outlet configured for
providing an outlet flow, and a plurality of flow channels coupled
between the inlet and the outlet. A flow distributor is provided for
distributing the inlet flow into the plurality of flow channels, so that
each flow channel receives a partial flow from the inlet flow. A flow
combiner is provided for combining the partial flows from the plurality
of flow channels to the outlet flow. Each flow channel comprises a first
flow section having a hydraulic resistance substantially constituting
entire hydraulic resistance of the flow channel for a partial flow. One
or more of the flow channels each comprises a second flow section coupled
in series with the first flow section of the respective flow channel.
Each second flow section has a volume delaying a propagation of the fluid
from the first flow section to the flow combiner by a time required by
the respective partial flow to pass the volume of the respective second
flow section. The distribution of the partial flows into the flow
channels is substantially independent of the viscosity of the fluid.

[0009] As the distribution of the partial flows in such embodiments is
substantially independent of the viscosity of the fluid, the mixer shows
an improved characteristic in particular in such applications wherein the
viscosity of the fluid varies over time. In HPLC, a typical application
with varying viscosity is the so-called gradient mode, wherein the
composition of the fluid is varied over time by changing the mixing ratio
for a plurality of different solvents over time. As an example, two
solvents water and acetonitrile (ACN; formula: CH3CN) might be mixed
for providing the mobile phase. During gradient mode, the mixing ratio
between water and acetonitrile is varied (e.g. continuously or stepwise)
over time, e.g. starting from hundred percent water to hundred percent
acetonitrile. Viscosity of the mixed fluid (here the mobile phase)
depends on the actual mixing ratio and thus becomes a function over time
during gradient mode.

[0010] With the independency of the distribution of the partial flows onto
the viscosity of the fluid, the mixing of the fluid as provided by the
mixer also becomes substantially independent on the viscosity of the
fluid, so that the mixer becomes in particular suitable and advantageous
for applications wherein the viscosity of the fluid varies over time,
such as in the aforementioned gradient mode in HPLC. Also, composition
change of the eluent with this mixer embodiment takes place in a
predictable and reproducible manner nearly independently on the special
properties of the solvents.

[0011] In one embodiment, the hydraulic resistance of each of the
plurality of flow channels is substantially equal. Accordingly, the
partial flows become equal for all channels thus providing a homogeneous
distribution of the partial flows into the flow channels.

[0012] In one embodiment, the volume of the second flow section is
significantly larger than a volume of the first flow section of the
respective flow channel. Accordingly, the hydraulic resistance of the
channel is dominated by the first flow section.

[0013] In one embodiment, the flow distributor distributes the fluid into
the first flow sections. Preferably, the flow distributor distributes the
fluid substantially simultaneously into the first flow section.

[0014] In one embodiment, the mixer is configured so that a variation of
the property of the fluid arrives substantially simultaneously at the
first flow sections. This can be achieved, for example, by arranging the
first flow sections to be coupled directly to the flow distributor, so
that the flow distributor simultaneously distributes the fluid into the
first flow sections of the flow channels.

[0015] In one embodiment, the mixer is configured in a way that the
flow-through times of the partial flows through the first flow sections
are substantially equal, so that all partial flows arrive substantially
at the same time at the respective second flow sections or, if a
respective flow channel does not have a second flow section, at the flow
distributor.

[0016] In one embodiment, the flow-through times of the partial flows
through the first flow sections are substantially neglectable to a
characteristic duration of a variation of the varying property of the
fluid. In other words, the property of the fluid is varying slower than
each partial flow requires to flow through the first flow section.

[0017] In one embodiment, the mixer is configured so that the flow-through
times of the partial flows through the first flow sections are
substantially equal and neglectable to a characteristic duration of a
variation of the varying property of the fluid. In such embodiment, the
partial flows reach the second flow sections or, in case the respective
flow channel does not comprise a second flow section, the flowed combiner
substantially at the same time and much faster than the property of the
fluid varies. Accordingly, it can be assumed that the mixing
characteristic of the mixer is dominated by the distribution of
characteristics of the second flow channels.

[0018] In one embodiment, a plurality of the second flow sections each has
a different volume for delaying the partial flow of the respective flow
channel by a different period. Accordingly, the resulting flow at the
flow combiner will show a certain distribution function as defined by the
respective delay volumes of the partial flows.

[0019] In one embodiment, the volume of each of a plurality of the second
flow sections is configured so that the output flow has a desired flow
delay profile with respect to the input flow.

[0020] In one embodiment, the volume of each second flow section is
significantly larger than a volume of the first flow section of the
respective flow channel. Thus, the timing behavior and in particular a
delay of the partial flow is dominated by the volume of the respective
second flow section.

[0021] In one embodiment, one or more of the second flow sections each
comprises a chamber having a volume being significantly larger than a
volume of the first flow section of the respective flow channel.

[0022] In another embodiment, one or more of the second flow sections each
comprises a plurality of chambers arranged sequentially, in parallel or
in a mixed connection pattern in the flow direction of the fluid. In one
embodiment, successive chambers are coupled by a respective connecting
section. Each chamber might have an (average or characteristic) cross
section being significantly larger than an (average or characteristic)
cross section of a respective connecting section coupled to such chamber.
Alternatively or in addition, each chamber might have a chamber volume
being significantly larger than a volume of a respective connecting
section coupled to such chamber. Alternatively or in addition, a
plurality of the connection sections can be arranged with respect to the
respective chambers to force the fluid to flow in a direction
sequentially varying respective to the direction of gravitational force.
In latter embodiments, the forcing of the flow in or against a direction
of a gravitational force can allow to provide embodiments, function of
which is substantially independent on the position of the mixer, so that
the mixing characteristics becomes substantially the same irrespective of
an actual position of the mixer with respect to the direction of
gravitational force. In such embodiments, it can be achieved that the
mixing performance of the mixer is substantially the same even if the
mixer is (arbitrarily) tilted/inclined with respect to a desired assembly
direction for such mixer.

[0023] In one embodiment one or more of the second flow sections each
comprises at least one direction change element configured for changing
the flow direction of the fluid. Preferably, the direction change element
comprises at least one first subsection having a first direction of flow
of the fluid, and at least one second subject section having a second
direction of flow of the fluid. The first direction of flow is inclined
with respect to the second flow section of flow. The first direction of
flow can be, for example, vertical, while the second direction of flow is
horizontal. Alternatively or in addition, at least one of the first and
second directions of flow has a direction component in the direction of
gravitational force. In other words, at least one of the first and second
directions is either in the direction of the gravitational force or being
inclined thereto by an angle less than ninety degrees (so that the effect
of gravity becomes noticeable). With such embodiments, the mixer can be
provided to have mixing properties being substantially independent on the
orientation of the mixer and the aforementioned (with respect to
orientation-independency) applies accordingly.

[0024] In one embodiment, each flow channel comprises a respective first
flow section and a respective second flow section coupled in series. The
hydraulic resistance of the first flow section is significantly larger
than a hydraulic resistance of the second flow section, so that the
hydraulic resistance of the flow channel is dominated by the first flow
section.

[0025] In one embodiment the hydraulic resistance of the first flow
section is in the range of 2-100000 times larger than the hydraulic
resistance of the second flow section. Preferably, the hydraulic
resistance of the first flow section is about 5-500 times larger than the
hydraulic resistance of the second flow section, and more preferably
about ten to hundred times.

[0026] In one embodiment, in each flow channel a first cross section of
the first flow section is significantly smaller than a second cross
section of the second flow section, so that the hydraulic resistance of
the flow channel is dominated by the first cross section of the first
flow section.

[0027] In one embodiment, each first flow section is substantially equal
in length in flow direction of the fluid. In other words, all first flow
sections are substantially equally long.

[0028] The fluid can be a liquid, a gas, a supercritical fluid, or
mixture.

[0029] The varying property of the fluid can be a physical and/or chemical
property varying along the flow direction of the fluid.

[0030] The varying property of the fluid can be temperature, composition,
and viscosity and/or elution strength varying along the flow direction of
the fluid. In case the fluid is comprised of plural fluid components,
e.g. different solvents such as water, acetonitrile, methanol, or
isopropanol, or it contains dissolved additives such as buffers, salts,
ion-pairing modifiers or other additives, e.g. TFA (trifluoroacetic acid,
the composition of the fluid describes the amount or ratio of each
individual fluid component present at a certain position or time along a
flow path of the fluid. Variations in composition can occur e.g. in case
a pump for pumping the fluid receives only one fluid component at a time
(wherein the pump sucks fluid into its pumping chamber) and takes in the
mixture components sequentially in the course of a pumping cycle. Such
"package-wise" supply of fluid with the individual packages, each having
a different fluid composition content, is commonplace in HPLC
applications, in particular during gradient mode, as disclosed e.g. in EP
309596 B1. Embodiments of the present invention allow mixing such
packages to provide a substantially homogeneous mixture of the fluid
components. Another source of composition variations can be transients in
the reciprocating operation of channels in a multi-channel pump, during
which the flows of the individual mixture components predestinated for
mixing are disturbed.

[0031] In one embodiment, a mixer is provided for mixing a fluid having a
property varying along a flow direction of the fluid. The mixer comprises
an inlet configured for receiving an inlet flow, an outlet configured for
providing an outlet flow, and a plurality of flow channels coupled
between the inlet and the outlet. A flow distributor is provided for
distributing the inlet flow into the plurality of flow channels so that
each flow channel receives a partial flow from the inlet flow. A flow
combiner is provided for combining the partial flows from the plurality
of flow channels to the outlet flow. Each flow path comprises a flow
direction changer forcing the fluid to flow first in direction changing
in respect to the direction of gravitational force. Such mixer provides a
mixing characteristic substantially independent of the spatial
orientation of the mixer with respect to the orientation of the
gravitational force. Accordingly, the mixing behavior of such mixer can
be provided to be less vulnerable or even independent of a respective
assembly or installation of the mixer in application.

[0032] In one embodiment a fluid separation system is provided for
separating compounds of a sample fluid in a mobile phase. When a mobile
phase including a fluidic sample passes through the fluidic device, for
instance driven by high pressure, the interaction between the column
packing and the fluidic sample may allow for separating different
components of the sample, as performed in a liquid chromatography device.

[0033] The fluid separation system comprises a mobile phase drive, such as
pumping system, configured to drive the mobile phase through the
separation system, and a separation unit, such as a chromatographic
column, configured for separating compounds of the sample fluid in the
mobile phase. The fluid separation system further comprises a mixer
according to any of the aforedescribed embodiments. The mixer can be
located anywhere along the flow path of the mobile phase with or without
the sample fluid. Preferably, the mixer is provided for mixing the mobile
phase before introduction of the sample fluid.

[0034] In still another embodiment a flow injection analysis system is
provided. In this case a mixer according to any of the afore described
embodiments is included into the flow path to provide mixing of the
sample components with reagents or with the flow provided through the
flow injection analysis system

[0035] Embodiments of the fluid separation system may comprise a sample
injector configured to introduce the sample fluid into the mobile phase,
a detector configured to detect separated compounds of the sample fluid,
a collection unit configured to collect separated compounds of the sample
fluid, a data processing unit configured to process data received from
the fluid separation system, and/or a degassing apparatus configured for
degassing the mobile phase.

[0036] Embodiments of the present invention might be embodied based on
most conventionally available HPLC systems, such as the Agilent 1290
Series Infinity system, Agilent 1200 Series Rapid Resolution LC system,
or the Agilent 1100 HPLC series (all provided by the applicant Agilent
Technologies--see www.agilent.com--which shall be incorporated herein by
reference).

[0037] The sample fluid might comprise any type of process liquid, natural
sample like juice, body fluids like plasma or it may be the result of a
reaction like from a fermentation broth. It may also comprise (but not
limited to) sea water, mineral oil or any rectification or cracking
fractions of it, extracts of soil, plants or artificial materials such as
plastics, as well as alcoholic or alcohol-free beverages.

[0038] The pressure in the mobile phase might range from 2-200 MPa (20 to
2000 bar), in particular 10-150 MPa (100 to 1500 bar), and more
particular 50-120 MPa (500 to 1200 bar).

[0039] Practically, the mixer with a number of flow path channels can be
built in a computable design, such as by a "parallel splitter" where an
incoming flow is immediately split to a number of channels, each having a
desired volume and hydraulic resistance determining the portion of the
flow passing through the channel; the distribution profile in the outlet
flow is entirely defined by the predesigned dead volumes of the
restrictor channels whereby the volume of the inlet chamber is
negligible. The above described restrictor channels can be of equal or
different hydraulic resistance.

[0040] The structure can be planar, the grooves of different width and
depth forming the desired system of reservoirs and restrictors. Any part
of the appliance can be non-planar, e.g. the restrictor drillings can
connect two sides of a plane block, bearing reservoir grooves on each
side.

[0041] The grooves in a planar structure can be wave-formed or curved to
improve radial mixing i.e. mixing of several eluent components flowing
side-by-side.

[0042] The structure can be of annular design, formed as a system of
parallel drillings in a cylinder block, one end of each drilling being
connected to the mixer inlet, the other end of each drilling being
connected to the mixer outlet. Each drilling consisting of two parts with
different diameters, the wider serving as a reservoir, the narrower
serving as a restrictor.

BRIEF DESCRIPTION OF DRAWINGS

[0043] Other objects and many of the attendant advantages of embodiments
of the present invention will be readily appreciated and become better
understood by reference to the following more detailed description of
embodiments in connection with the accompanied drawings. Features that
are substantially or functionally equal or similar will be referred to by
the same reference signs.

[0044] FIG. 1 shows a liquid separation system 10, in accordance with
embodiments of the present invention, e.g. used in high performance
liquid chromatography (HPLC).

[0045] FIG. 2 shows an embodiment of a mixer 200 according to the present
invention.

[0046] FIGS. 3A and 3B illustrate examples of mixing functions resulting
from an embodiment in according with FIG. 2.

[0047] FIG. 4 shows in cross sectional view an embodiment of a part of a
second flow section.

DETAILED DESCRIPTION

[0048] Referring now in greater detail to the drawings, FIG. 1 depicts a
general schematic of a liquid separation system 10. A pump 20 receives a
mobile phase from a solvent supply 25, typically via a degasser 27 which
reduces the amount of dissolved gases in the mobile phase. The pump
20--as a mobile phase drive--drives the mobile phase through a separating
device 30 (such as a chromatographic column) comprising a stationary
phase. A sampling unit 40 can be provided between the pump 20 and the
separating device 30 in order to introduce or add (often referred to as
introduce or inject) a sample fluid into the mobile phase. The stationary
phase of the separating device 30 is adapted for separating compounds
contained in the sample. A detector 50 can be provided for detecting
separated compounds of the sample. A fractionating unit 60 can be
provided for collection of separated compounds of the sample.

[0049] While the mobile phase can be comprised of one solvent only, it may
also be mixed from plurality of solvents. Such mixing might be a low
pressure mixing and provided upstream of the pump 20, so that the pump 20
already receives and pumps the mixed solvents as the mobile phase.
Alternatively, the pump 20 might comprise plural individual pumping
units, each of those receiving and delivering a different solvent or
mixture, so that the mixing of the mobile phase (as delivered to the
separating device 30) occurs at high pressure side and thus downstream of
the pump 20 (or within thereof). The composition of the mobile phase may
be kept constant over time, the so called isocratic mode, or varied over
time in a controlled manner, the so called gradient mode.

[0050] A control and data processing unit 70, which can be a conventional
PC, workstation or a dedicated controller, might be coupled (as indicated
by the dotted arrows) to one or more of the devices in the liquid
separation system 10 in order to receive information and/or to control
the operation. For example, the control and data processing unit 70 might
control operation of the pump 20 (e.g. setting control parameters) and
receive therefrom information regarding the actual working conditions
(such as output pressure, flow rate, etc. as measured within the
separation system 10 or at certain locations in the flow path, e.g.
within the pump unit 20). The data processing unit 70 might also control
operation of the solvent supply 25 (e.g. setting the solvent/s or solvent
mixture to be supplied) and/or the degasser 27 (e.g. setting control
parameters such as vacuum level) and might receive therefrom information
regarding the actual working conditions (such as pressure overtime, flow
rate, vacuum level, etc.). The data processing unit 70 might further
control operation of the sampling unit 40 (e.g. controlling sample
injection). The separating device 30 might also be controlled by the data
processing unit 70 (e.g. selecting a specific flow path or column,
setting operation temperature, etc.), and send--in return--information
(e.g. operating conditions) to the data processing unit 70. Accordingly,
the detector 50 might be controlled by the data processing unit 70 (e.g.
with respect to spectral or wavelength settings, setting time constants,
start/stop data acquisition), and send information (e.g. about the
detected sample compounds) to the data processing unit 70. The data
processing unit 70 might also control operation of the fractionating unit
60 (e.g. in conjunction with data received from the detector 50).

[0051] FIG. 2 shows an embodiment of a mixer 200 according to the present
invention. The mixer 200 is used for mixing a fluid property such as
composition, viscosity, elution strength or temperature, which might vary
along a flow direction of the fluid. While the mixer 200 can be situated
substantially anywhere in a fluid flow path where varying fluid
properties are expected, a preferred application is in the liquid
separation system 10 as schematically depicted in FIG. 1. In such liquid
separation system 10, the mixer 200 is preferably located in the flow
path between the pump 20 and the separating device 30, and more
preferably before the sampling unit 40. The mixer 200 may also be part
(e.g. integral, releaseably or non-releaseably attached) of one or more
components, such as the pump 20, the separating device 30, and the
sampling unit 40.

[0052] In the embodiment of FIG. 2, the mixer 200 comprises an inlet 210
receiving an inlet flow of the fluid to be mixed. A flow distributor 220
receives the flow from the inlet 210 and distributes it--in
parallel--into a plurality of flow channels 230. Accordingly, the flow
distributor 220 provides a plurality of parallel partial flows into the
plurality of (parallel) flow channels 230.

[0053] The flow distributor 220 of FIG. 2 is designed so that it
substantially simultaneously distributes the fluid into the first
sections 230 and/or that a variation of the property of the fluid arrives
substantially simultaneously at the first sections 260.

[0054] In the embodiment of FIG. 2, the flow distributor 220 comprises a
multi-stage configuration that provides simultaneous arrival of a given
partial fluid volume to all the restrictor channels in combination with
low distributor volume. Other embodiments are also possible in order to
achieve lowest total volume of the distributor.

[0055] The plurality of flow channels 230 eventually couple to a flow
combiner 240, which combines the partial flows from the plurality of flow
channels 230 and provides them to an outlet flow. The outlet flow is
output by an outlet 250. The flow combiner 240 is preferably designed to
provide a minimum volume, as such volume of the flow combiner 240
typically contributes mainly to delay and less to mixing properties.

[0056] Each of the plurality of flow channels 230 comprises a first flow
section 260, and some of the flow channels 230 further comprise a second
flow section 270 coupled in series to the respective first flow section
260. In the embodiment of FIG. 2, a first flow channel 230A comprises
(only) a first flow section 260A coupling directly between the flow
distributor 220 and the flow combiner 240. A second flow channel 230B
comprises a first flow section 260B coupling to a second flow section
270B, which then also couples into the flow combiner 240. Accordingly, a
third flow channel 230C comprises a first flow section 260C coupling into
a second flow section 270C, which then couples to the flow combiner 240.
This continues accordingly for further flow channels. In FIG. 2, further
first flow sections 260D-260L and second flow sections 270D-270L are
shown, each coupling in series and eventually to the flow combiner 240.

[0057] The first flow sections 260A-260L are designed to provide a
significantly larger hydraulic resistance than the respective second flow
section 270B-270L, so that the total hydraulic resistance of each flow
channel 230 is dominated by the hydraulic resistance of the respective
first flow section 260. Further in the specific embodiment of to FIG. 2,
all of the first flow sections 260A-260L are designed to have
substantially the same length and cross section, so that each first flow
section 260 substantially has the same hydraulic resistance. Considering
that the hydraulic resistance of each flow channel 230 is dominated by
its respective first flow section 260, it can be assumed that each flow
channel 230 can be regarded as providing substantially the same hydraulic
resistance to the fluid when introduced into the flow channels 230 at the
flow distributor 220. When designing the flow distributor 220 to
distribute the inlet flow substantially evenly into the flow channels
230, it can be assumed that the partial flow in each flow channel is
substantially equal. The distribution of the partial flows into the flow
channels 230 in such embodiment is substantially independent of the
viscosity of the fluid.

[0058] While the hydraulic resistance of each flow channel 230 is
dominated by its respective first flow section 260, each second flow
section 270 has a volume delaying fluid propagation (from the respective
first section 260 to the flow combiner 240) by a time required by the
respective partial flow to pass the volume of the respective second flow
section 270. In each flow channel 230, the volume of the second flow
section 270 is designed to be significantly larger than a volume of the
respective first flow section 260. In such embodiment, the propagation of
each partial flow will be mainly influenced by the volume of the
respective second flow section. By providing different volumes of the
respective second flow sections 270, a (desired) flow characteristic can
be obtained. By having at least one flow channel 230 without second flow
section, the total resulting flow characteristic of the mixer 200 can be
designed to have the minimum delay as resulting from the first flow
section 260 only.

[0059] FIG. 3A illustrates in an example a mixing function 300 depicting
the theoretical distribution of a very narrow (in terms of volume)
property variation in the fluid flow after the latter has passed through
the mixer over time or over the passed volume. The mixing function 300
may result from an embodiment in accordance with FIG. 2, however with the
difference that such mixer 200 providing the mixing function of FIG. 3A
shall have only ten flow channels 260 in contrast to the twelve flow
channels in the embodiments shown in FIG. 2. Each partial flow through
the flow channels 260 results in a partial flow profile 310A-310J, which
are then superimposed to the mixing function 300. Partial flow profile
310A shall result from a flow channel with only a first flow section such
as the first flow section 260A in FIG. 2, thus exhibiting the minimum
delay time of all partial flow profile 310A-310J. Partial flow profile
310B shall result from a flow channel with first and second flow sections
such as the first flow section 260B and the second flow section 270B in
FIG. 2. Correspondingly, flow profile 310C shall result from a flow
channel with first and second flow sections, such as the first flow
section 260C and the second flow section 270C. The second flow section
270C (corresponding to the flow profile 310C) is designed to have a
larger volume than the second flow section 270B, so that the flow profile
310C is further delayed (with respect to the flow profile 310A) than the
flow profile 310B. By designing each of the second flow sections 270 to
have a different volume, the flow functions 310B-310J each provide a
different delay with respect to the flow profile 310A resulting from the
propagation through the first flow section 260A only. By adequately
designing the respective volumes of the second flow section 270, many
different desired profile of the mixing function 30 can be achieved. It
is also clear that multiples of the second flow sections 270 may have a
same volume, so that a different that the substantially "flat" shape of
the mixing function 300 can be achieved.

[0060] FIG. 3B shows a mixing function 320 also resulting from a plurality
of partial flows with different delays. In contrast to the example of
FIG. 3A, the mixing function 320 of FIG. 3B shows an effect of increasing
dispersion for different channels, which represents the effect of the
dispersion of the property variation within a single partial flow as it
passes through its corresponding partial channel. The extent of this
additional distribution is determined by the partial channel design
(especially by the design of the second section).

[0061] FIG. 4 shows in cross sectional view an embodiment of the second
flow section, or at least a part thereof, as may be applied in the
embodiments of FIG. 2. It is noted that the partially three dimensional
illustration of FIG. 2, the second flow channels 270 are depicted
indicating a three-dimensional structure corresponding to FIG. 4.

[0062] In FIG. 4, the second flow channel 270 comprises a first chamber
500 and a second chamber 510 sequentially arranged in flow direction of
the fluid and coupled by a connection section 520. The chambers 500 and
510 provide a cross section in flow direction which is significantly
larger than the cross section of the connecting section 520. In the
depiction of FIG. 4, the cross section in flow direction is perpendicular
to the plain of the drawing. The volume of each of the first and second
chambers 500 and 510 is designed to be significantly larger than a volume
of the connecting section 520, so that a resulting flow delay is mainly
dominated by the volume of the chambers 500 and 510.

[0063] In the embodiment of FIG. 4, the flow entry (e.g. from the
respective first flow section) shall be at the top left side as denoted
with reference numeral 530, and fluid exit shall be at the top right side
as denoted with reference numeral 540 (e.g. to the flow combiner 240). As
apparent from FIG. 4, flow entry 530 is located in the first chamber 500
at the opposite side and height than the connecting section 520.
Accordingly, the fluid flow through the first chamber 500 is depicted by
arrow 550. With the connecting section 520 opening into the second
chamber 510 at opposing side and height than the flow exit 540, the flow
through the second chamber 510 will follow substantially as shown by
arrow 560. Arrow 570 shall represent the direction of gravitational
force.

[0064] In the embodiment of FIG. 4, the flow direction 550 in the first
chamber 500 has a component into the direction of the gravitational force
570, while the flow direction 560 shows a direction component in opposite
direction to the gravitational force 570. This also applies even if the
direction of gravitational force is tilted (by less than ninety degree in
each direction) with respect to the direction as indicated by arrow 570
in FIG. 4. Accordingly, the second flow section 270 of FIG. 4 provides a
direction change element for changing flow of the liquid with respect to
the gravitational force 570. Such forcing of the fluid to change
direction of flow with respect to gravitational force 570 can reduce or
even avoid the effect of fluid component sedimentation, which might occur
in larger volumes in case partial segments of not yet completely mixed
fluids have different density or specific gravity values and are thus
subject to sedimentation or separation in the gravitational field
according to their density. In such case, the forces caused by so-called
dynamic pressure differences applied to these partial segments should be
greater than the (Archimedes) force differences originating from the
specific gravity variation. One way to achieve this is to reduce the size
of "compact" fluid volumes by splitting a second section to a system of
interconnected chambers.

[0065] While a single chamber (to provide the second flow section 270)
might be sufficient in certain applications, it has been found that
plural chambers (as in FIGS. 2 and 4) allow designs having a higher
mechanical stability and also avoid that fluid components with different
density properties may separate within the chamber and lead to such
aforedescribed fluid component segmentation.

[0066] The mixer 200 (e.g. in FIG. 2) is preferably designed so that the
flow-through times of the partial flows through the first sections 260
are substantially neglectable as compared to a characteristic duration of
a variation of the varying property of the fluid. For example, in case of
an HPLC system as shown in FIG. 1 with the pump 20 producing liquid
packages of different composition, the mixer 200 is preferably designed
so that the flow-through time through the first section 260 is smaller
and preferably much smaller than a propagation time of the smallest
solvent composition package through the first section, and more preferred
through the mixer 200. This can be achieved by adapting the respective
cross sections lengths and volumes accordingly.

[0067] The restrictor channels of the first sections 260 may have
dimensions of about 0.1×0.12×20 mm. The second sections 270
(e.g. 0 to 24 chambers) may have dimension of 1 mm high and 0.8 mm or
smaller inner diameter.

[0068] It should be noted that the term "comprising" does not exclude
other elements or features and the "a" or "an" does not exclude a
plurality. Also elements described in association with different
embodiments may be combined. It should also be noted that reference signs
in the claims shall not be construed as limiting the scope of the claims.